Perspective Management of Advanced Fibrosis in the Context of Hepatitis C Virus Infection

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1 Perspetive Mngement of Advned Firosis in the Context of Heptitis C Virus Infetion Advned firosis my e present in sustntil proportion of individuls with symptomti, hroni heptitis C virus (HCV) infetion, inluding those who hve een newly dignosed. HCV tretment improves ll-use nd liver-relted mortlity in individuls with dvned firosis, nd there is some evidene tht reversl of deompensted liver disese my our in those with sustined virologi response. HCV tretment is lso ruil for individuls undergoing liver trnsplnttion, s reurrent HCV infetion posttrnsplnttion is ssoited with elerted firosis progression nd inresed risk of poor outomes. This rtile summrizes presenttion y Elizeth C. Vern, MD, t the IAS USA ontinuing edution progrm, Mngement of Heptitis C Virus in the New Er: Smll Moleules Bring Big Chnges, held in New York, New York, in Septemer Keywords: HCV, heptitis C virus, heptitis C, firosis, sustined virologi response, SVR, irrhosis, heptoellulr rinom, liver trnsplnttion Identifying Advned Firosis Currently, the most ommon methods for stging of firosis on liver iopsy speimens re the 4-point Metvir nd 6-point Ishk soring systems. A Metvir sore of F4 nd n Ishk sore of 6 indite irrhosis; Metvir sore of F2 nd n Ishk sore of 3 or 4 indite moderte firosis. Dt inditing tht even moderte firosis my e ssoited with worse outomes in the ontext of heptitis C virus (HCV) infetion ome from the HALT-C (Heptitis C Antivirl Long-Term Tretment Aginst Cirrhosis) tril, whih exmined the effet of mintenne therpy with peginterferon lf mong individuls with hroni HCV infetion nd firosis. The 6-yer umultive inidene of first linil event ws 5.6% for Ishk stge 2; 16.1% for Ishk stge 3; 19.3% for Ishk stge 4; 37.8% for Ishk stge 5; nd 49.3% for Ishk stge 6. 1,2 In report evluting ohort of 4 lrge provider networks, iopsy results or Firosis-4 (FIB-4) soring indited firosis of Metvir stge F2 or higher in more thn 50% of individuls without deompensted irrhosis who were ssessed for HCV tretment. 3 Thus, it is ommon for some individuls presenting to re for the first time fter HCV dignosis to lredy hve firosis even if they re symptomti nd hve lortory vlues nd physil exmintion findings within norml limits. Dr Vern is Assistnt Professor of Mediine t Columi University nd Diretor of Clinil Reserh t the Center for Liver Disese nd Trnsplnttion in New York, New York. Numerous serologi tests hve een developed to detet liver firosis, inluding the sprtte minotrnsferse (AST)- to-pltelet rtio index (APRI), FIB-4 soring, nd vrious serum iomrker tests. However, none of these tests is very sensitive or speifi, when used lone, for differentiting degree of firosis; they n e useful in determining the sene of firosis or presene of irrhosis ut re less useful in dignosing intermedite grdes of firosis. These tests my e even less urte for individuls who hve very mrked liver inflmmtion or ertin types of liver disese tht ffet the mrkers used in different wys. Stging of firosis using imging tehnology is likely to eome the stndrd of re in the oming yers. At present, the most ommon imging modlity in the United Sttes for stging of firosis is trnsient elstogrphy, ut other modlities inlude mgneti resonne elstogrphy (MRE), sher wve elstogrphy (SWE), nd ross-setionl imging. Trnsient elstogrphy, mjor dvne in the stging of firosis, generlly performs muh etter thn serologi mrkers nd mkes it esier to follow the sme individul s response to different therpies over time; however, it is not perfet. The dvntges of trnsient elstogrphy re tht it is inresingly ville, inexpensive, fst, nd preditive of linil outomes, nd tht it hs een tested in the ontext of mny disese stges. The disdvntges of trnsient elstogrphy re tht it is opertor dependent nd tht imging findings, s with ll types of ultrsound imging, my e skewed y ftors suh s n individul s ody hitus nd the presene of extensive inflmmtion or extensive ftty infiltrtion of the liver. MRE my e more urte ut is muh more expensive nd less ville t present thn trnsient elstogrphy. Conventionl ross-setionl imging nd ultrsound re onsidered indequte for urte stging of firosis. Trnsient elstogrphy vlues for eh firosis stge re shown in Tle 1. A omintion of serologi testing nd imging is likely the est option for stging of firosis t this time. Liver iopsy onfirmed the findings of serum iomrker testing Tle 1. Trnsient Elstogrphy Vlues for Eh Metvir Firosis Stge in Individuls With Chroni Heptitis C Virus Relted Liver Disese Trnsient Elstogrphy Vlue Metvir Firosis Stge kp F0-F1 (no or mild firosis) kp F2 (moderte firosis) kp F3 (severe firosis) >12.4 kp F4 (irrhosis) 7

2 IAS USA Topis in Antivirl Mediine Tle 2. Reommended Chnges to HCV Regimens for Tretment-Nive nd -Experiened Persons With Compensted Cirrhosis, y Genotype Regimen Tretment-Nive Persons Tretment-Experiened Persons HCV genotype 1 Dltsvir plus sofosuvir Elsvir/grzoprevir for No hnge No hnge Extend to 16- with or Ledipsvir/sofosuvir for No hnge Extend to or with rivirin dsuvir (with rivirin for genotype 1) for d Extend to for genotype 1 No hnge for genotype 1 Extend to for genotype 1 No hnge for genotype 1 Simeprevir plus sofosuvir with or Extend to Extend to HCV genotype 2 Dltsvir plus sofosuvir Extend to 16- with or HCV genotype 3 Dltsvir plus sofosuvir with or HCV genotype 4 Elsvir/grzoprevir for No hnge No hnge Ledipsvir/sofosuvir for No hnge Extend to or dd rivirin dsuvir for No hnge No hnge Arevition: HCV, heptitis C virus. Adpted from the Amerin Assoition for the Study of Liver Diseses nd the Infetious Diseses Soiety of Ameri. 5 Slsh indites oformultion. Regimen is reommended s n lterntive. For individuls with HCV genotype 1 infetion, if there re no seline resistne-ssoited vrints nd extend to 16 weeks if there re seline resistne-ssoited vrints. d This regimen is reommended for individuls with HCV genotype 1 infetion nd is n lterntive regimen with rivirin for individuls with HCV genotype 1 infetion. nd trnsient elstogrphy, used in omintion, for 84% of individuls with firosis of Metvir stge F2 or higher, 95% of those with Metvir stge F3 or higher, nd 94% of those with Metvir stge F4. 4 Although there remins role for liver iopsy, the er of routine liver iopsy to onfirm tht n individul does not yet require HCV tretment hs yielded to n er in whih liver iopsies re infrequent, refleting the eliefs tht ll HCV-infeted individuls should reeive tretment nd tht the risks ssoited with iopsy should e voided when possile. Liver iopsy still plys n importnt role when the findings of noninvsive tests re disrepnt or when other forms of hroni liver disese re suspeted. Widely used prognosti models for individuls with irrhosis inlude the Child-Turotte-Pugh (CTP) nd Model for End-Stge Liver Disese (MELD) sores. In generl, oth CTP nd MELD soring should e used to help determine the ppropriteness nd sfety of HCV tretment nd evlution for liver trnsplnttion. HCV Tretment Reommendtions for hnges in HCV tretment in individuls with ompensted irrhosis ording to HCV genotype re shown in Tle 2. 5 Extended durtion of tretment or the ddition of rivirin is reommended for mny regimens nd prtiulrly for tretment-experiened individuls with HCV genotype 1 disese, nd more hnges re reommended sed on HCV genotype sutype (1 vs 1). Similrly, extended tretment nd the ddition of rivirin re reommended for individuls with HCV genotype 2 or 3 disese nd ompensted irrhosis. An integrted nlysis of phse II nd III studies of tretment with ledipsvir/sofosuvir (slsh indites oformultion) with or for prtiipnts with HCV genotype 1 infetion nd ompensted irrhosis showed high rtes of sustined virologi response (SVR). 6,7 A somewht lower SVR rte ws oserved mong tretment-experiened prtiipnts who reeived only of ledipsvir/sofosuvir. Findings in the integrted nlysis indited little differene in SVR rtes ording to method of determintion of irrhosis, trnsient elstogrphy sore, or lumin level. However, SVR rtes were lower mong tretment-nive nd -experiened prtiipnts with pltelet ounts elow /µl, suggesting tht individuls with orderline deompensted irrhosis my hve een inluded in the studies nd in the nlysis. 8

3 Tle 3. Reommended HCV Regimens for Persons With Deompensted Cirrhosis, y Genotype HCV genotype 1 or 4 HCV genotype 2 or 3 Regimen Dltsvir plus sofosuvir plus rivirin Ledipsvir/sofosuvir plus rivirin Sofosuvir/velptsvir plus rivirin Dltsvir plus sofosuvir plus rivirin Sofosuvir/velptsvir plus rivirin Durtion ( ) (with rivirin for prior filed tretment with sofosuvir, or ) ( ) Arevition: HCV, heptitis C virus. Adpted from the Amerin Assoition for the Study of Liver Diseses nd the Infetious Diseses Soiety of Ameri. 5 Slsh indites oformultion. Low-dose rivirin strting t 600 mg dily nd inresed s tolerted. If rioflvin is ineligile. provements in ll-use mortlity (8.9% vs.0%), liver-relted mortlity or liver trnsplnttion (1.9% vs 27.4%), heptoellulr rinom (HCC; 5.1% vs 21.8%), nd liver filure (2.1% vs 29.9%). 10 Whether hepti deompenstion n e trnsformed into reompenstion fter n SVR hs een hieved hs not een definitively determined. However, some dt indite tht n SVR is ssoited with improvement in MELD or CTP sore in mny ut not ll individuls. 8 Nevertheless, some individuls hve progressive liver disese despite n SVR, nd little is known out how to determine whose disese will or will not progress. For individuls with deompensted irrhosis nd CTP lss B or C disese, hepti impirment represents ontrindition to the use of some nti-hcv drugs, inluding simeprevir, pritprevir (prt of the regimen of pritprevir/ ritonvir/omitsvir plus dsuvir), nd grzoprevir (prt of the regimen of elsvir/grzoprevir), owing to degree of hepti metolism nd reports of liver injury. Current reommendtions for HCV tretment for individuls with deompensted irrhosis re shown in Tle 3. 5 Mny of the reommended regimens inlude rivirin, refleting the gol of improving the hnes for n SVR despite the potentil worsening of nemi in some individuls. Some experts suggest inititing rivirin t 600 mg (not weight sed) nd titrting the dose ording to tolerility. The est dt on tretment with ledipsvir/sofosuvir plus rivirin for individuls with CTP lss B or C disese ome from the SOLAR-1 nd SOLAR-2 studies (Figure 1). 8,9 There ws no mrked differene in SVR 100 rtes with 12 or of tretment, nd there ws some suggestion of lower SVR rtes mong prtiipnts 80 with CTP lss C disese. The sfety profile ws quite fvorle, prtiulrly given the degree of illness in these 60 prtiipnts. Adverse events of ny grde inluded ftigue (41%), nemi (20%), nd hedhe (27%), nd 40 grde 3 or 4 dverse events ourred in 24% of prtiipnts; 4% of prtiipnts disontinued due to dverse 20 events. No deths were onsidered to e relted to the 0 study drugs. Impt of SVR on Tretment Outomes Findings from severl studies hve mde it ler tht SVR in individuls with dvned firosis is ssoited with redued risk of hepti deompenstion nd deth. In n nlysis of 530 individuls with dvned firosis, SVR versus no SVR ws ssoited with im- SVR12 (%) 9 Complitions of Cirrhosis nd Evlution for Liver Trnsplnttion Complitions of irrhosis inlude HCC nd omplitions of portl hypertension, suh s vriel leeding, enephlopthy, heptorenl syndrome, nd syntheti dysfuntion. Suh omplitions hve mrked impt on disese prognosis nd should prompt n evlution for liver trnsplnttion. Sreening is reommended for vriel leeding nd HCC for ll individuls with irrhosis, euse erly intervention n led to etter outomes. An esophgogstroduodenosopy (EGD) should e performed t the time of dignosis of irrhosis to sreen for vriel leeding, with surveillne intervl depending on linil sttus: EGD should e repeted every 2 to 3 yers for individuls with ompensted irrhosis CTP B Figure 1. Rtes of sustined virologi response fter esstion of tretment with oformulted (/) ledipsvir/sofosuvir plus rivirin mong heptitis C virus infeted prtiipnts with Child-Turotte-Pugh (CTP) lss B or C disese in the SOLAR-1 nd SOLAR-2 studies. Effiy ws omprle etween the 2 studies. Adpted from Chrlton et l nd Mnns et l. 8,9 86 SOLAR-1 81 CTP C 87 SOLAR-2 /30 22/ 24/27 24/25 19/22 17/21 20/23 19/25 76

4 IAS USA Topis in Antivirl Mediine SOLAR-1 SOLAR SVR12 (%) / 55 49/ 52 55/ 56 No Cirrhosis 49/ 49 25/ 33/ 34 24/ 25 32/ 33 CTP A 22/ 21/ 22 23/ CTP B 23/ 23 3/5 1/3 3/4 4/5 4/4 3/3 2/2 2/2 CTP C FCH Figure 2. Rtes of sustined virologi response fter esstion of tretment with oformulted (/) ledipsvir/sofosuvir plus rivirin mong heptitis C virus (HCV)-infeted individuls with HCV genotypes 1 nd 4 post liver trnsplnttion, y Child-Turotte-Pugh (CTP) lss in the SOLAR-1 nd SOLAR-2 studies. Adpted from Chrlton et l nd Mnns et l. 8,9 who hve no vries, every 1 to 2 yers if smll vries re present, nd nnully for individuls with deompensted irrhosis. Nonseletive β-lokers or nd ligtion (for very lrge esophgel vries) my e used to sustntilly redue the inidene of vriel hemorrhge. Individuls with HCV-relted irrhosis should e sreened for HCC vi ultrsound every 6 months, s there is evidene tht sreening for HCC in high-risk popultions, inluding those with virl heptitis infetion, is ssoited with redued mortlity. 11,12 HCC n still our in the ontext of n SVR. In some ses, HCC my e present ut reltively undetetle efore initition of HCV tretment. Lol-regionl therpy for HCC is not onsidered to e urtive, lthough some individuls who undergo hemoemoliztion do not pper to experiene reurrene. Sreening for HCC using α-fetoprotein (AFP) testing lone is no longer reommended, s it is not onsidered sensitive or speifi enough nd sustntil proportion of individuls with HCC hve norml results on AFP testing. The urrent inditions for liver trnsplnttion in the ontext of HCV disese re the presene of irrhosis or MELD sore of 15 or higher nd ny deompensting event (eg, HCC, sites, hepti enephlopthy, vriel hemorrhge, or heptopulmonry syndrome). Tretment for HCV infetion in liver trnsplnt reipients is ruil euse the nturl history of reurrent HCV infetion fter trnsplnttion is elerted (irrhosis ours in up to 25% of individuls y 5 to 10 yers fter liver trnsplnttion, 10 nd omplitions of irrhosis re more ommon). SVR improves survivl rtes mong liver trnsplnt reipients. In n idel world, ll HCV-infeted individuls would reeive tretment nd hieve n SVR efore liver trnsplnttion, eliminting the risk for reurrene. In relity, n SVR is not lwys hieved efore liver trnsplnttion, nd response rtes in individuls with CTP lss C disese re lower thn in other sugroups reeiving HCV tretment, inluding in those with ompensted irrhosis posttrnsplnt. Further, depending on the region of the United Sttes, ess to new orgn my e diffiult for individuls in whom HCV tretment hs lered the virus (eg, if MELD sore drops from 27 to 18 fter HCV tretment in n Tle 4. HCV Regimens Post Liver Trnsplnttion Inluding Ptient With Reurrent Compensted Cirrhosis Reommended for HCV genotype 1 or 4 Alterntives for HCV genotype 1 Reommended for HCV genotype 2 or 3 Regimen Dltsvir plus sofosuvir with or Ledipsvir/sofosuvir with or without rivirin dsuvir nd rivirin Simeprevir plus sofosuvir with or Dltsvir plus sofosuvir plus rivirin Sofosuvir plus rivirin Durtion (with rivirin) () (with rivirin) () (with rivirin) () Arevition: HCV, heptitis C virus. Adpted from the Amerin Assoition for the Study of Liver Diseses nd the Infetious Diseses Soiety of Ameri. 5 Slsh indites oformultion. Currently reommended for persons with HCV genotype 2 infetion or deompensted reurrent liver disese. Only reommended for ptients with erly stge reurrent firosis (F0-2).

5 individul with deompensted irrhosis, tht individul my e ineligile for liver trnsplnttion in some lotions). Thus, ommunition with lol trnsplnt groups regrding individuls with moderte MELD sore ut severl disese omplitions in whom it is elieved tht HCV tretment will not hieve omplete reompenstion should e onsidered. Dt re now emerging on the use of periopertive tretment immeditely efore or fter liver trnsplnttion. A smll phse II study exmined tretment with sofosuvir plus rivirin given immeditely efore trnsplnttion to individuls with ny HCV genotype, HCC, nd CTP lss A or B disese. 13 Among 43 evlule prtiipnts, 65% hieved posttrnsplnttion VR. However, periopertive tretment is not generlly reommended t this time due to high relpse rtes with sofosuvir plus rivirin in individuls with HCV genotype 1 infetion. It is not known whether this pproh would e more effetive with urrently reommended regimens. More reently, smll group of individuls ws treted with ledipsvir/sofosuvir in the immedite postopertive setting for only 4 weeks, nd SVR ws hieved in 14 of 16 individuls. 14 Importnt onsidertions regrding HCV tretment immeditely fter liver trnsplnttion inlude potentil drug-drug intertions with nti-hcv drugs, prtiulrly etween HCV protese inhiitors nd lineurin inhiitors (eg, ylosporine, trolimus), nd the potentil need for tretment interruption due to omplitions in the setting of high-dose immunosuppression. Most experiene with HCV tretment in the posttrnsplnttion setting is with ledipsvir/sofosuvir plus rivirin (in prt euse of the lower likelihood of drug intertions thn with other HCV regimens). Dt from the SOLAR-1 nd SOLAR-2 studies mong prtiipnts with HCV genotype 1 or 4 infetion show tht HCV tretment during the erly period fter liver trnsplnttion produed high SVR rtes fter esstion of tretment (SVR12) in those with CTP lss A or B disese (Figure 2); lthough rtes were lower in those with CTP lss C disese, SVR ws still hieved in the mjority of prtiipnts. 8,9 Current reommendtions for HCV tretment fter liver trnsplnttion re shown in Tle 4. 5 Conlusion Individuls with dvned firosis nd liver trnsplnt reipients re mong those with the highest priority for HCV tretment owing to their high risk for severe omplitions. SVR mong individuls with dvned liver disese my redue the risk of life-thretening deompenstion. However, even individuls with irrhosis nd preserved liver funtion remin t risk for deompenstion nd must e monitored indefinitely. Sfe nd effetive HCV tretment with diretting ntivirl drugs hs revolutionized the re of liver trnsplnttion ndidtes nd reipients with HCV infetion, lthough tretment must urrently e individulized sed on stge of disese, omoridities, nd ess to liver llogrft. Presented y Dr Vern in Septemer First drft prepred from trnsripts y Mtthew Stenger. Reviewed nd edited y Dr Vern in Ferury Finnil ffilitions in the pst 12 months: Dr Vern hs reeived grnts wrded to her institution from Slix Phrmeutils, In. Referenes 1. Dienstg JL, Ghny MG, Morgn TR, et l. A prospetive study of the rte of progression in ompensted, histologilly dvned hroni heptitis C. Heptology. 2011;54(2): Everhrt JE, Wright EC, Goodmn ZD, et l. Prognosti vlue of Ishk firosis stge: findings from the heptitis C ntivirl long-term tretment ginst irrhosis tril. Heptology. 2010;51(2): Xu F, Wrd JW, Holmerg SD, Gordon SC. Ptients meeting "highest" or "high" priority for HCV tretment in the hroni heptitis hort study (CHeCS) [Astrt LB-29]. 65th Annul Meeting of the Amerin Assoition for the Study of Liver Diseses. Novemer 7-11, 2014; Boston, Msshusetts. 4. Cster L, Vergniol J, Fouher J, et l. Prospetive omprison of trnsient elstogrphy, Firotest, APRI, nd liver iopsy for the ssessment of firosis in hroni heptitis C. Gstroenterology. 2005; 128(2): AASLD/IDSA. HCV guidne: reommendtions for testing, mnging, nd treting heptitis C. Aessed Ferury 14, Bourliere M, Sulkowski MS, Omt M, et l. An integrted sfety nd effiy nlysis of >500 ptients with ompensted irrhosis treted with ledipsvir/sofosuvir with or [Astrt 82]. 65th Annul Meeting of the Amerin Assoition for the Study of Liver Diseses. Novemer 7-11, 2014; Boston, Msshusetts. 7. Reddy KR, Bourliere M, Sulkowski M, et l. Ledipsvir nd sofosuvir in ptients with genotype 1 heptitis C virus infetion nd ompensted irrhosis: An integrted sfety nd effiy nlysis. Heptology. 2015;62(5): Chrlton M, Everson GT, Flmm SL, et l. Ledipsvir nd sofosuvir plus rivirin for tretment of HCV infetion in ptients with dvned liver disese. Gstroenterology. 2015;149(3): Mnns M, Smuel D, Gne EJ, et l. Ledipsvir nd sofosuvir plus rivirin in ptients with genotype 1 or 4 heptitis C virus infetion nd dvned liver disese: multientre, open-lel, rndomised, phse 2 tril. Lnet Infet Dis. 2016;16(6): vn der Meer AJ, Veldt BJ, Feld JJ, et l. Assoition etween sustined virologil response nd ll-use mortlity mong ptients with hroni heptitis C nd dvned hepti firosis. JAMA. 2012; 308(24): Zhng BH, Yng BH, Tng ZY. Rndomized ontrolled tril of sreening for heptoellulr rinom. J Cner Res Clin Onol. 2004;130(7): Singl AG, Pilli A, Tiro J. Erly detetion, urtive tretment, nd survivl rtes for heptoellulr rinom surveillne in ptients with irrhosis: met-nlysis. PLoS Med. 2014;11(4):e Curry MP, Forns X, Chung RT, et l. Sofosuvir nd rivirin prevent reurrene of HCV infetion fter liver trnsplnttion: n openlel study. Gstroenterology. 2015;148(1): Levitsky J, Vern EC, O'Lery JG, et l. Periopertive ledipsvirsofosuvir for HCV in liver-trnsplnt reipients. N Engl J Med. 2016;375(21): Top Antivir Med. 2017;25(1): , IAS USA. All rights reserved 11